ProjectNeurobehavioral Mechanisms of Cognitive and Affective Impairment from Fetal Exposure to Superfund Chemicals
Project Leader: Edward Levin
Publications ↓Project Description
A variety of chemicals on the Superfund list, such as pesticides, metals and polyhalogenated hydrocarbons have been found to impair cognitive function, including learning, memory and attention. Dr. Levin and his research team have focused on determining the neural mechanisms underlying the cognitive impairments caused by developmental pesticide exposure. Using the classic rat model of developmental neurobehavioral toxicology, they have shown in the first funding period of this center that the organophosphate insecticide chlorpyrifos causes persistent effects on working and reference memory.
The researchers have taken a two-stage approach to determine the neural underpinnings of these effects. Neurochemical studies in the Slotkin lab have demonstrated the chlorpyrifos-induced disruptions of cholinergic, catecholaminergic and serotonergic transmitter systems. Neurobehavioral studies in the Levin lab have demonstrated with pharmacological probes that developmental chlorpyrifos exposure disrupts the functional role played by muscarinic acetylcholine systems in memory function. The researchers extended study of developmental chlorpyrifos effects on cognitive function to zebrafish to better understand the molecular effects underlying this impairment. They found with zebrafish that chlorpyrifos exposure during development causes persisting cognitive impairment. Initial studies with morpholino suppression of acetylcholinesterase show cognitive impairments in zebrafish. These studies will determine the neural mechanisms underlying chlorpyrifos-induced effects on learning, attention and emotional response.
Specific tests of learning (repeated acquisition), attention (operant signal detection) and anxiety (elevated plus maze) will be used together with pharmacological probes of choliriergic, catecholaminergic and serotonergic transmitter receptor systems to determine not only the impact of chlorpyrifos on these neurobehavioral functions but also to determine the functional role of these transmitter systems in the persisting neurobehavioral effects of chlorpyrifos. Initial studies will be made concerning the specificity of these effects to chlorpyrifos or generality to other organophosphate pesticides. Zebrafish studies will provide critical information of how pesticides affect molecular controls over cognitive development.
Description ↑Publications
Levin ED, OA Timofeeva, L Yang, A Petro, IT Ryde, N Wrench, FJ Seidler and TA Slotkin. Early postnatal parathion exposure in rats causes sex-selective cognitive impairment and neurotransmitter defects which emerge in aging. Behavioural Brain Research, 208:319-327. 2010. PMC2831164
Eddins D, D Cerutti, P Williams, E Linney and ED Levin. Zebrafish provide a sensitive model of persisting neurobehavioral effects of developmental chlorpyrifos exposure: comparison with nicotine and pilocarpine effects and relationship to dopamine deficits. Neurotoxicology and Teratology, 32:99-108. 2010. PMC in process
Slotkin TA, N Wrench, IT Ryde, TL Lassiter, ED Levin and FJ Seidler. Neonatal parathion exposure disrupts serotonin and dopamine synaptic function in rat brain regions: Modulation by a high-fat diet in adulthood. Neurotoxicology and Teratology, 31:390–399. 2009. PMC2761992
Slotkin TA, TL Lassiter, IT Ryde, N Wrench, ED Levin and FJ Seidler. Consumption of a high-fat diet in adulthood ameliorates the effects of neonatal parathion exposure on acetylcholine systems in rat brain regions. Environmental Health Perspectives, 117:916-922. 2009. PMC2702406
Lassiter TL, IT Ryde, EA MacKillop, BE. Bodwell, KK Brown, ED Levin, FJ Seidler and TA Slotkin. Exposure of neonatal rats to parathion elicits sex-selective reprogramming of metabolism and alters the response to a high-fat diet in adulthood. Environmental Health Perspectives, 116:1456-1462. 2008. PMC2592263
Crofton KM, JA Foss, U Hass, K Jensen, ED. Levin and SL Parker. 2008. Undertaking positive control studies as part of developmental neurotoxicity testing. Neurotoxicology and Teratology.in press.
Timofeeva OA, CS Roegge, FJ Seidler, TA Slotkin and ED Levin. 2008. Persistent cognitive alterations in rats after early postnatal exposure to low doses of the organophosphate pesticide, diazinon. Neurotoxicology and Teratology. 30:28-45.
Slotkin TA, IT Ryde, ED Levin and FJ Seidler. 2008. Developmental neurotoxicity of low-dose diazinon exposure of neonatal rats: Effects on serotonin systems in adolescence and adulthood. Brain Research Bulletin. 75:640-647.
Slotkin TA, BE Bodwell, ED Levin and FJ Seidler. 2008. Neonatal exposure to low doses of diazinon: Long-term effects on neural cell development and acetylcholine systems. Environmental Health Perspectives. 116:340-348 .
Eddins D, A Petro, N Pollard, JH Freedman and ED Levin. 2008. Mercury-induced cognitive impairment in metallothionein knockout mice. Neurotoxicology and Teratology. 30:88-95.
Roegge CS, OA Timofeeva, FJ Seidler, TA Slotkin and ED Levin. 2007. Developmental diazinon neurotoxicity in rats: Later effects on emotional response. Brain Research Bulletin. 75:166-172.
Levin ED, Z Bencan and DT Cerutti. 2007. Anxiolytic effects of nicotine in zebrafish. Physiology and Behavior. 90:54-58.
Slotkin, T.A. and F.J. Seidler. 2007. Prenatal chlorpyrifos exposure elicits presynaptic serotonergic and dopaminergic hyperactivity at adolescence: critical periods for regional and sex-selective effects. Reproductive Toxicology. 23: 421-427.
Slotkin, T.A., E.A. MacKillop, I.T. Ryde, C.A. Tate and F.J. Seidler. 2007. Screening for developmental neurotoxicity using PC12 cells: comparisons of organophosphates with a carbamate, an organochlorine and divalent nickel. Environmental Health Perspectives. 115: 93-101.
Levin ED, C Perraut, N Pollard and JH Freedman. 2006. Metallothionein expression and neurocognitive function in mice. Physiology and Behavior. 87:513-518.
Cerutti DT and ED Levin. 2006. Cognitive impairments models using complementary species. In: Animal Models of Cognitive Impairment. ED Levin and JJ Buccafusco, (eds.), pp. 315-342, CRC Press, New York.
Slotkin TA, ED Levin and FJ Seidler. 2006. Comparative developmental neurotoxicity of organophosphate insecticides: Effects on brain development are separable from systemic toxicity. Environmental Health Perspectives. 114:746-751.
Slotkin TA, CA Tate, IT Ryde, ED Levin and FJ Seidler. 2006. Organophosphate insecticides target the serotonergic system in developing rat brain regions: disparate effects of diazinon and parathion at doses spanning the threshold for cholinesterase inhibition. Environmental Health Perspectives. 114:1542-1545.
Aldridge JE, ED Levin, FJ Seidler and TA Slotkin. 2005. Developmental exposure to chlorpyrifos elicits behavioral alterations in adulthood, involving serotonergic mechanisms and resembling animal models of depression. Environmental Health Perspectives. 113:527-531.
Icenogle L, NC Christopher, WP Blackwelder, DP Caldwell, D Qiao, FJ Seidler TA Slotkin and ED Levin. 2004. Behavioral alterations in adolescent and adult rats after a brief subtoxic exposure to chlorpyrifos during neurulation. Neurotoxicology and Teratology 26:95-101.
Levin ED, HA Swain, S Donerly and E Linney. 2004. Developmental chlorpyrifos effects on hatchling zebrafish swimming behavior. Neurotoxicology and Teratology. 26:719-723.
Levin ED, E Crysthansis, K Yacisin and E Linney. 2003. Chlorpyrifos exposure of developing zebrafish: Effects on survival and long-term effects on response latency and spatial discrimination Neurotoxicology and Teratology. 25:51-57.
Levin ED, N Addy, A Baruah, A Elias, NC Christopher, FJ Seidler and TA Slotkin. 2002. Prenatal chlorpyrifos exposure in rats causes persistent behavioral alterations. Neurotoxicology and Teratology. 24:733-741.
Levin ED, N Addy, A Nakajima, NC Christopher, FJ Seidler and TA Slotkin. 2001. Persistent behavioral consequences of neonatal chlorpyrifos exposure in rats. Developmental Brain Research. 130:83-89.